Investigating the neural circuits and molecular mechanisms which regulate emotional behaviour and cognitive affective bias

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The role of emotions in cognitive function is an important area of neuroscience but one where our understanding is limited. Observations of animals and humans have shown that emotions can modify behaviour. In animals, these types of behaviours are classically studied by looking at fear behaviours such as freezing or escape, or reward behaviours such as reward learning. How emotions affect behaviour is much more complex than this and recent developments in the methods used to study emotional behaviour in animals suggest complex and subtle effects of both positive and negative emotional states on cognition. Studies in humans have shown that the emotional state can influence the way they experience their environment and also the decisions they make. These are often referred to as cognitive affective biases. These biases have been shown to influence attention, learning and memory, recall, interpretation and decision-making and dysfunction in these process are linked to emotional disorders. Recently, methods have been developed which have enabled researchers to show that similar cognitive affective biases are found in animals and that emotional state (often referred to as affective state in animals) can induce optimistic or pessimistic cognitive behaviours in animals as diverse as honey bees, mice, rats, sheep, dogs and primates.Our research project takes forward the advances in methods to study emotional behaviour using animals and focusses on one aspect of cognitive affective bias: the impact of emotions on decision-making. Our research group has been one of leaders in the development of the judgement bias task for rodents. In this task animals are trained to associated specific cues with an emotional outcome, either positive or negative. Once these reference cues are learnt, cognitive affective biases are tested by presenting the animal with an intermediate ambiguous cue and observing how the animal responds. Optimistic animals make more responses in anticipation of the positive event whilst pessimistic animals make more responses in anticipation of the negative event. We can then manipulate the animal's emotional state and observe how the bias in this task changes. We have already shown that this type of methodology relates well to behaviour in humans as we have tested an almost identical task in human participants. We have also made an exciting discovery when looking at antidepressant drugs in this task and found that the effectiveness, and rate of onset of action of the treatments used in people, is mirrored closely in this test. For example, the delayed onset antidepressant fluoxetine does not immediately make rats more optimistic but does if the dosing is given daily for more than a week. This, and the recent discovery that the rapid onset antidepressant, ketamine, can make rats immediately more optimistic in this task forms the basis for the proposed studies in this application.Our aim is to take forward these discoveries and build towards a better understanding of the brain mechanisms which cause these optimistic versus pessimistic behaviours. Our proposed experiments will use different drug treatments and direct manipulations of small regions of the brain to try to understand the brain circuits which regulate emotional behaviour. We will also be able to utilise the expertise and additional resources provided by our industrial collaborator to undertake a much more sophisticated analysis of specific pathways and neuronal sub-populations in key regions of interest. These studies will combine genetic manipulations with gene sequencing studies and are anticipated to yield a detailed insight into the molecular and neural circuits. These will help identify novel drug targets to take forward for further validation and potentially into a drug development programme.